Bioinformatics: Literature Searchlight

The time and cost required to bring a new drug to market can exceed 10 years and $800 million, according to the Tufts Center for the Study of Drug Development. Now researchers at etexx Biopharmaceuticals in Dallas, Texas, are using software that they say will slash this time and cost. How? By mining the medical literature for hints on new uses for drugs already approved by the Food and Drug Administration. 
 
Repurposing existing drugs can offer substantial payoffs for both pharmaceutical companies and the public. For example, bupropion has been licensed separately as an antismoking drug (Zyban) and an antidepressant (Wellbutrin); Rogaine, now used to treat hair loss, was originally developed as a treatment for high blood pressure. 
 
The software was created at The University of Texas (UT) Southwestern Medical Center by biochemistry professor Harold Garner and colleagues, and has been licensed to etexx, which Garner founded. Known as IRIDESCENT (for Implicit Relationship IDEntification by in-Silico Construction of an Entity-Based Network from Text), the program allows full-scale automated analysis of records in MEDLINE, the National Library of Medicine’s bibliographic database. Eventually the software could be used with other online resources such as the Physicians’ Desk Reference and even internal documents from pharmaceutical and biotech companies. 
 
The software analyzes MEDLINE abstracts to identify and evaluate statistical relationships among biomedical terms such as names of genes, phenotypes, drugs, and diseases. The program compares how often sets of these terms appear in texts relative to random probability. It can identify and compare over 300,000 different biomedical terms along with their spelling variations, synonyms, and acronyms. A network of these “co-mentions” is created and then analyzed by a statistical program to find indirect or implicit connections. 
 
IRIDESCENT then scores the objects for relevance, significance, and interest, allowing the researcher to inspect the resulting connections to trigger hypotheses on new uses for existing drugs. The team showed the value of this approach by validating in several lab trials a connection between the drug Thorazine, used to treat psychotic disorders, and a reduction in the progression of cardiac hypertrophy, or enlargement of the heart, which the program had predicted. The results were published 12 February 2004 in Bioinformatics. 
 
Besides conducting its own lab research on potential repurposed drugs, etexx will help pharmaceutical and genomics organizations sort through existing data and generate hypotheses from high-throughput data processes such as microarrays or proteomics mass spectroscopy analysis. “Everyone is trying to find ways to develop drugs cheaply,” says Stephen Johnston, director of the UT Southwestern Center for Biomedical Inventions, which develops new drugs and procedures. “Garner has had very promising preliminary results.”


ore a prior
ty in treatment of whiplash injuries.

Definitions of whiplash and associated conditions vary between published studies.The Quebec Task Force (QTF) definitions are internationally recognised and are used in this study [4].Whiplash is the mechanism of injury (acceleration-deceleration injuries usually in the frontal plane), whiplash injuries are the soft tissue injuries that result and Whiplash Associated Disorder (WAD) describes the pattern of symptoms that arise (Table 1).A further term, late whiplash syndrome, is used to describe the chronic complications of whiplash.

Despite whiplash being a common injury, there are few good quality randomised trials pon which to base recommendations for practice [5].In the mid 1990s the QTF undertook an extensive review and expert consensus exercise [4], and found that there was insufficient evidence supporting the treatments currently used.They concluded that promoting activity in the early stages was probably the most effective strategy, soft collars were not helpful, and physiotherapy, a very common treatment, required rigorous evaluation.The QTF proposed a clinical pathway in which patients are given advice and education at the initial contact and then reviewed at three weeks.Patients with persisting symptoms would then be provided with more intensive treatment.

A stepped care clinical pathway as proposed by the QTF is the model evaluated in this trial.The advice and education component to be evaluated is The Whiplash Book [6].This has been developed largely based on the results of a systematic review [7], which suggested that psychological risk factors are the strongest predictors of poor outcome in whiplash patients, and argued that advice to resume normal activity, using a cognitive-behavioural approach, should be the treatment of choice for early management.However, other systematic reviews have suggested that physical and psychological factors may carry equivalent amounts of r sk for poor outcome [8].Furthermore, most of the literature cited to support the early activity and key health promotion messages was from the field of low back pain and ther chronic conditions.It is questionable whether these results are transferable to acute whiplash injuries, as the conditions differ markedly in their causes and psychological consequences.For example, phobic travel anxiety and other psychological manifestations of shock are common after whiplash [9], but rarely occur with low back pain.

The second component of the stepped care approach evaluated in MINT is physiotherapy for patients whose symptoms have not resolved by three weeks.Physiotherapy treatments that are commonly used for whiplash patients include hot and cold therapy, electrotherapies, mobilisation, manipulation, exercises of many different kinds, and traction.There is good quality trial evidence to support the effectiveness of mobilisation and exercise in the management of chronic neck pain [10][11][12], but it is uncertain whether these treatments are effective for whiplash patients.The Cochrane review of conservative treatments for whiplash [4] concl ded that there was some evidence that active treatments are superior to passive, though the existing trials were not of high quality.Another review concluded that there was moderate quality evidence that exercises and mobilisations commonly used by physiotherapists were effective [13], but this was based on just three small trials, which reported short-term outcomes only, did not perform intention to treat analyses, and did not have blinding of outcome assessment.For evaluation in MINT we have designed a package of physiotherapy treatments that, according to current evidence, are those most likely to be effective in prevention of late whiplash syndrome and to be acceptable to practitioners.


Current practice

A national survey of practice in the UK indicated that the most common treatment for whiplash in emergency departments (ED) is advice, but the content and quality of the advice varies [unpublished data].Over 90% of departments suggest using analgesics and gradually increasing movement of the neck.Some departments use soft collars as well, suggesting that they should be removed and the neck exercised on a regular basis.


Methods

MINT is a multi-centre randomised controlled trial to estimate the clinical effectiveness of a stepped care approach to whiplash injuries on clinical outcomes over 12 months, the effectivenes

in pre-specified
ub-groups of patients (those with severe physical symptoms, prior neck problems, psychological or physical risk factors for poor outcome, and those seeking compensation), and the costs and cost-effectiveness of each strategy.

The trial will use two separate randomisations: the first stage is a cluster randomised trial in which NHS Trusts are randomised to use the Whiplash Book or give their usual advice, for all patients

resentin
with whiplash injuries.The second stage is individual randomisation to physiotherapy or the control intervention of a single advice session reinforcing the advice given in ED, for patients still experiencing whiplash symptoms at three weeks.The two parts of the trial have a common system of follow-up at four, eight and 12 months.


Stage 1: Cluster randomised trial of the whiplash book versus usual advice Inclusion and exclusion cri eria

All people who attend ED with a whiplash injury of less than six weeks duration will be included in the trial, except those with any of the following exclusion criteria:

1. Age less than 18 years.

2. Fractures or dislocations of the spine or other bones.

3. Head injuries with more than a transient loss of consciousness or with a Glasgow Coma Score of 12 or less at any stage of their assessment in hospital.

4. Admission to in-patient services.

5. Severe psychiatric illness.


Identifying participants and consent

Because the firs

part of the trial is cluster randomised, individual consent for participati
n is not sought.This is an accepted procedure for cluster randomised trials where individuals do not have a choice of whether to receive the trial intervention [14].All eligible patients at each particip ting hospital are included nless they indicate that they do not wish to participate i data collection.

Clinicians in ED are responsible for identifying eligible participants.Details of whiplash patients are recorded on the trial proforma, short form developed specifically fo

methods of clinical data collection i
participating centres.It is intended to avoid duplication of recording of information for clinical and research purposes, and hence allows collection of a routine core clinical data set, including injury severity, pain intensity and WAD grade diagnosis.It contains tick boxes to ensure that clinicians have provided potential participants with the trial information sheet and have discussed the study wit them, and also records if the patient would prefer not to receive the study questionnaires.The proforma is self-copying; one copy is filed in the medical notes as a treatment record and the second copy is passed to the research team to notify them that a patient has been asked to participate.Completed proformas are collected in a secure place in the ED and forwarded to the MINT research team twice a week.

Patients are informed about the possibility that they may be eligible for stage 2 of the study but detailed information about this is not given at this stage, as the majority of patients who participate in stage 1 will not have persistent symptoms at 3 weeks and hence will not be eligible for stage 2. Patients are also asked for their contact details (address, phone number, mobile phone and email), to assist with sending out and following up questionnaires.


Randomisation

The unit of randomisation is the NHS Trust.Participating Trusts were randomised before the start of recruitment by the project statisticians, to usual advice or the Whiplash B ok.Trusts were pair matched on size (number of ED attendances per year), star rating, and ethnic composition of the surrounding area.We randomised by Trust rather than by ED to avoid contamination when staff of one Trust worked in more than one ED.Randomisation used a table of random numbers, starting at a random place to ensure that the allocations were not known before randomisation.The allocation depended on whether the next digit was even or odd.One of e

h pair was ran
omised to the Whiplash Book, and the other member was allocated to usual advice.


Delivery of interventions

Training of ED staff in the trial procedures is given before the start of recruitment, and there is frequent contact between the centres and the trial team to identify and resolve any problems.Eligible patients are given a letter of introduction about the study, signed by their local ED consultant, and the study is discussed with them.If they are willing to participate, they are told that they will receive a questionnaire in a few days time.They are asked to return this and to contact the MINT study team if they continue to have problems after two weeks.The introduction letter does not mention randomisation of hospitals to T

Whiplash Book or usual ad
ice, but simply states that the hospital is taking part in a study of advice given to patients with whiplash injuries.ED clinicians provide a copy of either the ED's usual advice leaflet or the Whiplash Book, and verbal guidance on management of whiplash injuries.We have obtained copies of the usual advice leaflets from all of the EDs participating in MINT, so that the content of the advice in the control arm can be documented.


Baseline data collection

All whiplash patients that are eligible for MINT and have not asked to be excluded are sent a copy of the MINT baseline questionnaire within a week of their ED attendance.This includes demographic information and baseline administration of some of the outcome measures.If the questionnaire is not returned within a week, participants are sent a reminder by SMS text message, email or post.


Stage 2: Individually randomised trial of physiotherapy versus reinforcement of advice given in ED Identifying participants and consent

Participants in Stage 1 are asked to contact the study office if they continue to have symptoms two weeks afte

their attendance at ED.An
appointment is then made for the patient with a research physiotherapist based at their local hospital.At this appointment, their eligibility for Stage 2 of the trial is assessed.If eligible, trial participation is discussed and the patient is asked to sign a study consent form prior to randomisation.Information about Stage 2 of MINT is sent to patients several days before their research c

nic appointment, ensuring that they have sufficient time to consider participation.


Inclusion and exclusion criteria

Participants in
tage 1 of MINT are eligible for the second part of the trial if they:

• Report symptoms in the 24 hours before attendance at the physiotherapy research clinic approximately three weeks after attendance at ED Participants who are randomised to the physiotherapy package have up to six sessions of therapy, over an eight week period.The components of the intervention are described in a training and reference manual.The choice of physiotherapy treatments has been made using two principles; first, there is evidence that the treatments are effective for chronic neck dysfunction and are likely to be effective for whipla

injuries, based on expert opinio
or limited trial evidence, and second, the treatments target established and potential y modifiable risk factors for developing late whiplash syndrome, including reduced cervical range of motion, high pain intensity, and adve se psychological reactions to the injury.

Three treatments are included in the physiotherapy package:

(1) Mobilisation (gentle manipulation) of the cervical and upper thoracic spine according to Maitland [15].

(2) Exercises for the cervical spine, thoracic spine and shoulder t

improve range
f movement and muscle control.

(3) A cognitive behavioural approach to treatment delivery, which has been effective in physiotherapy for other painful conditions [16].

Manipulation (Maitland Grade IV) of the cervical spine is excluded from this treatment package.Both whiplash injury and cervical manipulation have the potential to cause damage to the vertebral artery that may result in a cerebrovascular event.In common with some, but not all, authorities we consider that recent trauma is a contraindication to cervical manipulation.


(

Reinforcement
of advice

Participants randomised to reinforcement of advice receive a single 40-minute session of advice from a physiotherapist.At this session, the physiotherapist re-states the advice that the patient was given at the time of their ED attendance (either the Whiplash Book or the hospital's usual advice), discusses any queries that the patient may have, and may check the exercises that the patient was given in ED.The physiotherapist can only give advice regarding progression of exercises or acti

ties specified in
he Whiplash Book or usual advice.They cannot prescribe new exercises or use any "hands on" treatment.No review appointments are offered to these patients.They are advised to see their GP if they have ongoing problems.


Other treatments

Participants may seek other forms of treatment during the follow up period from their GP or other health professionals.If the trial interventions are effective, this should be evident in a reduction in additional treatments.Such treatments, including changes in the amount or types of analgesia used, use of physical treatments (osteopathy, chiropractic or physiotherapy), alternative therapies, or referral to secondary care services will be recorded as a treatment outcome.


Ou come measures and data collection

Follow-up data collection is by postal questionnaire.The outcome measures are detailed in Table 2.The primary outcome is return to nor al function after the whiplash injury, measured using the Neck Disability Index (NDI).

The NDI is a self-completed questionnaire that has been used successfully in a postal format in trials of neck treatments [10,17].It assesses pain-related activity r strictions in 10 areas including personal care, lifting, sleeping, driving, concentration, reading and work.The SF-12 and EQ-5D are included to assess generic health-related quality of life, and to enable a single utility score for economic evaluation to be derived from the EQ-5D.Participants also rate whether they have improved, remained the same, or worsened, and the r satisfaction with treatment.Resource use is assessed by a short questionnaire which asks about additional NHS or private hospital treatment for the whiplash injury, any GP consultations, manipulation, massage or other treatment.Participants are asked to distinguish between prescription and out-of-pocket expenses.Participants are asked at 12 month follow-up whether they have pursued and settled a compensation claim related to their whiplash injury.It is not asked at 4 or 8 month follow-up to avoid stimulation of claims among the trial population.

A research assistant who has not been involved in the recruitment or randomisation processes is responsible for mailing follow up questionnaires, and for entering responses onto the study database.Blinding of

he study team wil
be maintained until final analysis of the data has been completed.


Statistical analysis

The analysis will be by intention to treat.All patients will be analysed in the groups to which they were randomised, regardless of the treatment that they actually received.The two main comparisons will be Whiplash Book versus usual advice, and physiotherapy package versus reinforcement of ED advice.The comparison of ED advice interventions will use appropriate methods to take accou

of the cluster randomisation [18].Es
imates of treatment effect with 95% confidence intervals, and the numbers needed to treat, will be reported.Additional exploratory analyses will investigate whether there is an interaction between the ED advice intervention and physiotherapy.

Four pre-specified subgroup analyses will be undertaken:

1. severe physical symptoms at trial entry (WAD Grade III versus WAD Grade I or II)

2. adverse psychological reactions at trial entry (yes/no) 3. pre-existing neck pain versus no pre-existing neck pain


compensation; claim being pursued versus not being pursued

Statistical tests of interaction will be used to perform subgroup analyses [19].

Economic analysis will use cost-minimisation, or costeffectiveness and cost-utility analysis, depending on the clinical results.For cost-utility analysis, the EQ-5D will be used to generate utility scores, which will provide an estimate of the incremental cost of any benefit gained in terms of improved health status.Decision modelling will be used to investigate the costs and benefits of the different patient management routes, and uncertainty will be quantified by multi-way sensitivity analyses [20].


Sample size

For the primary outcome of NDI, there is consensus that a minimal clinically importance difference lies in the range of 3-5 percentage points, with a st ndard deviation of about 8% [8].We therefore aim to be able to detect a difference between the groups of three percentage points (i.e.0.375 standard deviations), both for the comparison of the Whiplash Book and usual advice, and for physiotherapy versus reinforcement of advice.For the individuall

randomised comparison
(physiotherapy versus reinforcement of advice), 211 per group will be required, based on 90% power and 1% significance level.Assuming a worst case scenario of 30% loss to follow-up gives a total sample size of 300 per group (600 in total) [21].The comparison of ED advice interventions is cluster randomised, so larger numbers are needed.Originally it was planned that eight centres would participate, recruiting 4,800 participants.This was revised with the inclusion of four additional centres, which allowed reduction of the overall sample size required to achieve the same power.Assuming an intracluster correlation co-efficient of 0.02, and an average of 120 patients pe centre gives an inflation factor of 5.94 [22], leading to a sample size of 713 in each group.Allowing for 30% loss to follow up, 1020 par icipants per group will be needed (2040 in total).To allow for a reduction in power caused by unequal sample sizes among clusters, the target sample size has been set to 3000 (an average of 250 per cluster).The assumptions underlying the sample size calculation will be monitored by the DMEC during recruitment and adjustments may be made during the course of the trial.

Table 1 : Case definitions of Whiplash Associated Disorders Term Definition
1WAD Grade 0No neck complaints or signsWAD Grade IComplaint o

pain, stiffn
ss or tenderness, but no physical signsWAD Grade IIComplaint of pain, stiffness or tenderness, and musculo-skeletal signs (decreased range of motion, point tenderness etc)WAD Grade IIIComplaint of pain, stiffness or tenderness and neurological signs (decreased or absent deep tendon reflexes, weaknessand sensory deficits). Could also have musculo-skeletal signs.WAD Grade IVFracture or dislocationLate whiplash syndrome Presence of pain, restriction of motion or other symptoms at six months or more after the injury, sufficient to hinderreturn to normal activities such as driving, usual occupation and leisure.

Table 2 : Outcome measures
2Domain
*all outcome measures are collected by self-completed postal questionnaires

(page number not for citation purposes)
AcknowledgementsMINT study teamInvestigators: Prof S Lamb, Prof MW Cooke, Dr S Gates, Prof M Underwood, Prof D Ashby, Prof A Szczepura, Dr S Joseph, Dr FE Griffiths.FundingMINT is funded by the NHS R&D Health Technology Assessment Programme, project number 02/35/02.Competing interestsThe author(s) declare that they have no competing interests.Authors' contributionsSEL designed the study, secured funding and contributed to writing the paper.SG contributed to protocol revisions and drafted the paper.MRU contributed to design of the study and securing funding and revised the paper.MWC contributed to design of the study and securing funding and revised the paper.DA was responsible for statistical aspects of study development, contributed to securing funding and revised the paper.AS was responsible for economic aspects of study development, contributed to securing funding and revised the paper.P e-publication historyThe pre-publication history for this paper can be accessed here: htt ://www.biomedcentral.com/1471-2474/8/7/prepub
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Whiplash injury: clinical r view. L Barnsley, S Lord, N Bogduk, Pain. 581994

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